Transgenic animal model of neurodegenerative disorders

Abstract

The present invention provides a transgenic animal model of Alzheimer's Disease designated TgCRND8 as well as a method for making such model, which allows for the characterization of the etiology of the disease as well as for provide a system for the development and testing of potential treatments.

1. A transgenic mouse produced by:
 (a) crossing a first transgenic mouse whose genome comprises a transgene comprising a nucleotide sequence operably linked to a Syrian hamster prion protein gene promoter and encoding a human amyloid precursor protein 695 (APP695) polypeptide wherein the lysine residue at position 670 is substituted by asparagine, the methionine residue at position 671 is substituted by leucine and the valine residue at position 717 is substituted by phenylalanine, and wherein the transgene is expressed, 
 with a second mouse having a genome comprising a second gene comprising a nucleotide sequence operably linked to a promoter and encoding a selected protein having at least one selected mutation, and wherein the gene is expressed, to produce first generation offspring; and 
 (b) selecting from the first generation offspring a transgenic mouse having a genome comprising at least one first transgene comprising a nucleotide sequence operably linked to a Syrian hamster prion protein gene promoter and encoding a human APP695 polypeptide wherein the lysine residue at position 670 is substituted by asparagine, the methionine residue at position 671 is substituted by leucine and the valine residue at position 717 is substituted by phenylalanine, and at least one second gene comprising a nucleotide sequence operably linked to a promoter and encoding said selected protein having at least one selected mutation, wherein at least both the first transgene and the second gene are expressed and expressing both said at least one first transgene and said at least one second gene. 
 
     
     
       2. A transgenic mouse, or its progeny, whose genome comprises at least one first transgene comprising a nucleotide sequence operably linked to a Syrian hamster prion protein promoter and encoding a human APP695 polypeptide wherein the lysine residue at position 670 is substituted by asparagine, the methionine residue at position 671 is substituted by leucine and the valine residue at position 717 is substituted by phenylalanine, and at least one second gene comprising a nucleotide sequence operably linked to a promoter and encoding said selected protein having at least one selected mutation, wherein at least both the first transgene and the second gene are expressed. 
     
     
       3. The transgenic mouse of  claim 1  or  2 , wherein said mouse is a (C3H×C57BL6)×C57 mouse. 
     
     
       4. The transgenic mouse of  claim 1  or  2 , wherein said second gene is a mutant endogenous gene. 
     
     
       5. The transgenic mouse of  claim 1  or  2 , wherein said second gene is a transgene. 
     
     
       6. The transgenic mouse of  claim 1  or  2 , wherein said second gene comprises a nucleotide sequence encoding a heterologous presenilin protein. 
     
     
       7. The transgenic mouse of  claim 1  or  2 , wherein said second gene comprises a nucleotide sequence encoding a protein selected from the group consisting of: a low density lipoprotein receptor related gene, an α2-macroglobulin gene and a β-secretase gene, and wherein the selected mutation is an Aβ processing-related mutation. 
     
     
       8. The transgenic mouse of  claim 6 , wherein said heterologous presenilin protein is a presenilin 1 or a presenilin 2 protein. 
     
     
       9. The transgenic mouse of  claim 8 , wherein said presenilin 1 or presenilin 2 protein comprises an AD-related amino acid substitution. 
     
     
       10. The transgenic mouse of  claim 6 , wherein said heterologous presenilin protein is a presenilin 1 protein, wherein the leucine residue at position 286 is substituted by valine. 
     
     
       11. The transgenic mouse of  claim 6 , wherein said heterologous presenilin protein is a presenilin 1 protein, wherein the methionine residue at position 146 is substituted by leucine and the leucine residue at position 286 is substituted by valine. 
     
     
       12. The transgenic mouse of  claim 6 , wherein said heterologous presenilin protein is a presenilin 2 protein, wherein the methionine residue at position 239 is substituted by valine.